Extravascular lung water (EVLW) is a sensitive prognostic indicator of pulmonary edema. Thus, EVLW may be an advantageous method of fluid management. This study aims to evaluate the outcomes of using EVLW and pulmonary artery wedge pressure (PAWP) as strategies for fluid management in patients with acute respiratory distress syndrome (ARDS).
Twenty-nine patients were randomly divided into the EVLW and PAWP groups. The survival rate, ICU (Intensive Care Unit) length of stay, duration of mechanical ventilation, acute lung injury scores, and oxygenation index of the EVLW and PAWP groups were compared.
No significant difference in the survival rates at 28 and 60 days (d) after treatment was found between the two groups (p = 0.542). The duration of mechanical ventilation and ICU length of stay were significantly lower (p < 0.05) in the EVLW group than in the PAWP group. The 7 d cumulative fluid balance was -783 ± 391 ml in the EVLW group and -256 ± 514 ml in the PAWP group (p < 0.05). Compared with the PAWP group, the EVLW group showed improved oxygenation index (p = 0.006).
EVLW for fluid management improved clinical results in patients with ARDS better than PAWP.
Acute respiratory distress syndrome; Extravascular lung water; Fluid management; Pulmonary artery wedge pressure
Bone marrow-derived stem cells (BMSCs) are locally adjacent to the tumor tissues and may interact with tumor cells directly. The purpose of this study was to explore the effects of BMSCs on the proliferation and invasion of osteosarcoma cells in vitro and the possible mechanism involved.
BMSCs were co-cultured with osteosarcoma cells, and CCK-8 assay was used to measure cell proliferation. The ELISA method was used to determine the concentration of stromal cell-derived factor-1 (SDF-1) in the supernatants. Reverse transcription polymerase chain reaction (RT-PCR) was performed to detect the expression of CXCR4 in osteosarcoma cells and BMSCs. Matrigel invasion assay was performed to measure tumor cell invasion.
SDF-1 was detected in the supernatants of BMSCs, but not in osteosarcoma cells. Higher CXCR4 mRNA levels were detected in the osteosarcoma cell lines compared to BMSCs. In addition, conditioned medium from BMSCs can promote the proliferation and invasion of osteosarcoma cells, and AMD3100, an antagonist for CXCR4, can significantly downregulate these growth-promoting effects.
BMSCs can promote the proliferation and invasion of osteosarcoma cells, which may involve the SDF-1/CXCR4 axis.
Bone marrow mesenchymal stem cells; Osteosarcoma
The liver has a strong regenerative capacity. After injury, quiescent hepatocytes can reenter the mitotic cell cycle to restore tissue homeostasis. This G0/G1-S cell-cycle transition of primed hepatocytes is regulated by complexes of cyclin-dependent kinase 2 (Cdk2) with E-type cyclins (CcnE1 or CcnE2). However, single genetic ablation of either E-cyclin or Cdk2 does not affect overall liver regeneration. Here, we systematically investigated the contribution of CcnE1, CcnE2, and Cdk2 for liver regeneration after partial hepatectomy (PH) by generating corresponding double- and triple-knockout (KO) mouse mutants. We demonstrate that conditional deletion of Cdk2 alone in hepatocytes resulted in accelerated induction of CcnE1, but otherwise normal initiation of S phase in vivo and in vitro. Excessive CcnE1 did not contribute to a noncanonical kinase activity, but was located at chromatin together with components of the pre-replication complex (pre-RC), such as the minichromosome maintenance (MCM) helicase. Concomitant ablation of Cdk2 and CcnE1 in hepatocytes caused a defect in pre-RC formation and further led to dramatically impaired S-phase progression by down-regulation of cyclin A2 and cell death in vitro and substantially reduced hepatocyte proliferation and liver regeneration after PH in vivo. Similarly, combined loss of CcnE1 and CcnE2, but also the Cdk2/CcnE1/CcnE2 triple KO in liver, significantly inhibited S-phase initiation and liver mass reconstitution after PH, whereas concomitant ablation of CcnE2 and Cdk2 had no effect.
In the absence of Cdk2, CcnE1 performs crucial kinase-independent functions in hepatocytes, which are capable of driving MCM loading on chromatin, cyclin A2 expression, and S-phase progression. Thus, combined inactivation of Cdk2 and CcnE1 is the minimal requirement for blocking S-phase machinery in vivo.
Stem cell-derived hepatocyte-like cells hold great potential for the treatment of liver disease and for drug toxicity screening. The success of these applications hinges on the generation of differentiated cells with high liver specific activities. Many protocols have been developed to guide human embryonic stem cells (hESCs) to differentiate to the hepatic lineage. Here we report cultivation of hESCs as three-dimensional aggregates that enhances their differentiation to hepatocyte-like cells. Differentiation was first carried out in monolayer culture for 20 days. Subsequently cells were allowed to self-aggregate into spheroids. Significantly higher expression of liver-specific transcripts and proteins, including Albumin, phosphoenolpyruvate carboxykinase, and asialoglycoprotein receptor 1 was observed. The differentiated phenotype was sustained for more than 2 weeks in the three-dimensional spheroid culture system, significantly longer than in monolayer culture. Cells in spheroids exhibit morphological and ultrastructural characteristics of primary hepatocytes by scanning and transmission electron microscopy in addition to mature functions, such as biliary excretion of metabolic products and cytochrome P450 activities. This three-dimensional spheroid culture system may be appropriate for generating high quality, functional hepatocyte-like cells from ESCs.
To determine the position and dose delivery changes rules of parotid gland (PG) during the course of intensity modulated radiation therapy (IMRT) in nasopharyngeal carcinoma patients (NPC).
Materials and methods
One hundred and forty one competed tomography (CT) images from 47 NPC patients (three images for each patient were acquired before treatment, at the 15th and 25th fraction during the treatment) who underwent radical IMRT were selected for this study. A total of 70-76Gy at 2.12–2.3 Gy/fraction/d was given to the GTVnx in 33 fractions. The distances between the lateral/medial aspects of PG and midline (DLM and DMM) at the level of odontoid process were measured. The dose differences between plan and actual delivery were calculated.
The volume reductions of PGs between fractions 15 and 25 were larger than those in the first 15 fractions (4.68 ± 3.23 cc vs. 2.46 ± 4.55 cc for the right PG and 5.96 ± 2.99 cc vs. 2.06 ± 2.99 cc for the left PG). However, the percentage of gland volume receiving ≥30 Gy (V30) of bilateral PGs decreased more significantly in the first 15 fractions than that between fractions 15 and 25 (5.61 ± 16.04% vs. 1.14 ± 21.54% for the right PG and 6.87 ± 15.58% vs. 0.81 ± 15.94% for the left PG). The gross tumor volume of the nasopharynx (GTVnx) decreased more significantly in the first 15 fractions than that between the 15th and 25th fraction (8.23 ± 13.61 cc vs. 3.30 ± 8.09 cc). The DMM of ipsilateral PGs reduced in the first 15 fractions (0.80 ± 2.96 mm) but increased between fraction 15 and 25 (−2.19 ± 3.96 mm). While ipsilateral PG shifted into target volume but shifted out target volume between fraction 15 and 25. Parotid glands V30 was correlated with GTVnx, GTVnx reduction and DMM reduction (p < 0.01).
Our results indicate that the reduction of GTVnx leads to the positional change of the parotid gland, which results in more significant dose change of the parotid gland in the first 15 fractions than that between fraction 15 and 25.
Nasopharyngeal carcinoma; Intensity-modulated radiotherapy; Parotid gland
Pituitary adenomas, monoclonal in origin, are the most common intracranial neoplasms. Altered gene expression as well as somatic mutations is detected frequently in pituitary adenomas. The purpose of this study was to detect differentially expressed genes (DEGs) and biological processes during tumor formation of pituitary adenomas. We performed an integrated analysis of publicly available GEO datasets of pituitary adenomas to identify DEGs between pituitary adenomas and normal control (NC) tissues. Gene function analysis including Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis, and protein-protein interaction (PPI) networks analysis was conducted to interpret the biological role of those DEGs. In this study we detected 3994 DEGs (2043 upregulated and 1951 downregulated) in pituitary adenoma through an integrated analysis of 5 different microarray datasets. Gene function analysis revealed that the functions of those DEGs were highly correlated with the development of pituitary adenoma.
This integrated analysis of microarray data identified some genes and pathways associated with pituitary adenoma, which may help to understand the pathology underlying pituitary adenoma and contribute to the successful identification of therapeutic targets for pituitary adenoma.
The WHO declared the 2014 west African Ebola epidemic a public health emergency of international concern in view of its potential for further international spread. Decision makers worldwide are in need of empirical data to inform and implement emergency response measures. Our aim was to assess the potential for Ebola virus to spread across international borders via commercial air travel and assess the relative efficiency of exit versus entry screening of travellers at commercial airports.
We analysed International Air Transport Association data for worldwide flight schedules between Sept 1, 2014, and Dec 31, 2014, and historic traveller flight itinerary data from 2013 to describe expected global population movements via commercial air travel out of Guinea, Liberia, and Sierra Leone. Coupled with Ebola virus surveillance data, we modelled the expected number of internationally exported Ebola virus infections, the potential effect of air travel restrictions, and the efficiency of airport-based traveller screening at international ports of entry and exit. We deemed individuals initiating travel from any domestic or international airport within these three countries to have possible exposure to Ebola virus. We deemed all other travellers to have no significant risk of exposure to Ebola virus.
Based on epidemic conditions and international flight restrictions to and from Guinea, Liberia, and Sierra Leone as of Sept 1, 2014 (reductions in passenger seats by 51% for Liberia, 66% for Guinea, and 85% for Sierra Leone), our model projects 2·8 travellers infected with Ebola virus departing the above three countries via commercial flights, on average, every month. 91 547 (64%) of all air travellers departing Guinea, Liberia, and Sierra Leone had expected destinations in low-income and lower-middle-income countries. Screening international travellers departing three airports would enable health assessments of all travellers at highest risk of exposure to Ebola virus infection.
Decision makers must carefully balance the potential harms from travel restrictions imposed on countries that have Ebola virus activity against any potential reductions in risk from Ebola virus importations. Exit screening of travellers at airports in Guinea, Liberia, and Sierra Leone would be the most efficient frontier at which to assess the health status of travellers at risk of Ebola virus exposure, however, this intervention might require international support to implement effectively.
Canadian Institutes of Health Research.
Dendritic cells (DCs) function as professional antigen presenting cells and are critical for linking innate immune responses to the induction of adaptive immunity. Many current cancer DC vaccine strategies rely on differentiating DCs, feeding them tumor antigens ex vivo, and infusing them into patients. Importantly, this strategy relies on prior knowledge of suitable “tumor-specific” antigens to prime an effective anti-tumor response. DCs express a variety of receptors specific for the Fc region of immunoglobulins, and antigen uptake via Fc receptors is highly efficient and facilitates antigen presentation to T cells. Therefore, we hypothesized that expression of the mouse IgG1 Fc region on the surface of tumors would enhance tumor cell uptake by DCs and other myeloid cells and promote the induction of anti-tumor T cell responses. To test this, we engineered a murine lymphoma cell line expressing surface IgG1 Fc and discovered that such tumor cells were taken up rapidly by DCs, leading to enhanced cross-presentation of tumor-derived antigen to CD8+ T cells. IgG1-Fc tumors failed to grow in vivo and prophylactic vaccination of mice with IgG1-Fc tumors resulted in rejection of unmanipulated tumor cells. Furthermore, IgG1-Fc tumor cells were able to slow the growth of an unmanipulated primary tumor when used as a therapeutic tumor vaccine. Our data demonstrate that engagement of Fc receptors by tumors expressing the Fc region of IgG1 is a viable strategy to induce efficient and protective anti-tumor CD8+ T cell responses without prior knowledge of tumor-specific antigens.
Fc receptors; IgG1; dendritic cells; cross-presentation; CD8 T cell priming; cancer vaccine; MHC Class I
Antimicrobial resistance of Neisseria gonorrhoeae is a serious health problem in China. Gonococcal antimicrobial susceptibility has been monitored in Shanghai since 1988. In this study, we examined the changing pattern of gonococcal antimicrobial susceptibility based on data from N. gonorrhoeae isolates collected over the past 25 years.
Approximately 100–200 isolates each year (1988–2013) were tested for their susceptibility to penicillin (PEN), tetracycline (TET), ciprofloxacin (CIP), ceftriaxone (CRO) and spectinomycin (SPT), using the agar dilution method. Plasmid-mediated N. gonorrhoeae antimicrobial resistance, comprising penicillinase-producing N. gonorrhoeae (presumed PPNG) and high-level tetracycline resistance N. gonorrhoeae (presumed TRNG), were also determined. Breakpoints for susceptibilities followed those described by the Clinical and Laboratory Standard Institute and the European Committee on Antimicrobial Susceptibility Testing.
A high proportion of isolates were resistant to PEN, TET and CIP, ranging from less than 20% at the beginning of the survey, increasing in the late 1990s and reaching over 90% in recent years. The proportion of isolates exhibiting plasmid-mediated resistance exceeded 38% for presumed PPNG and 20% for presumed TRNG in recent years. The proportion of CRO nonsusceptible isolates (MIC ≥ 0.125 mg/L) ranged from 7% to 13% in most of the study years. Almost all isolates were susceptible to SPT. The SPT MIC90 was 16–32 mg/L for 2008–2013. The proportion of CRO nonsusceptible-associated multiple-drug-resistant (MDR) isolates was over 5% in most of the study years.
N. gonorrhoeae isolates in Shanghai were resistant to PEN, TET and CIP. Furthermore, CRO nonsusceptible and MDR isolates were prevalent. N. gonorrhoeae isolates were also found to be susceptible to SPT. It is recommended that the CRO dose be increased from currently recommended 250 mg to 500 mg and that SPT be an alternative in treating urogenital gonorrhea. Our findings highlight the importance of both regional and national surveillance programs for the prompt modification of treatment guidelines, vital in responding to the changing pattern of gonococcal antimicrobial susceptibility.
Electronic supplementary material
The online version of this article (doi:10.1186/s12879-014-0731-9) contains supplementary material, which is available to authorized users.
Neisseria gonorrhoeae; Antimicrobial susceptibility; Multiple drug resistance; Ceftriaxone; Spectinomycin
AIM: To evaluate the potential prognostic value of GNAS1 T393C polymorphism in advanced non-small cell lung cancer.
METHODS: We extracted genomic DNA from the peripheral blood leucocytes of 94 patients with advanced non-small cell lung cancer. Quantitative real-time polymerase chain reaction was used to determine the allelic discrimination. The correlation between genotype and overall survival was evaluated using the multivariate analysis and Kaplan-Meier approach.
RESULTS: Thirty-eight out of 94 (40%) patients displayed a TT genotype, 29 out of 94 (31%) a CT genotype and 27 out of 94 (29%) a CC genotype. The median survival of TT (25 mo) genotype carriers was longer than CT (12 mo) or CC (8 mo) genotype carriers. The favorable TT genotype predicted better overall survival (OS) (2-year OS: 48%; P =0.01) compared with CT (2-year OS: 18%) or CC (2-year OS: 15%) genotype. However, dichotomization between C-genotypes (CC + CT) and T-genotypes (TT) revealed signiﬁcantly lower survival rates (2-year OS: 16%; P = 0.01) for C allele carriers.
CONCLUSION: Our data provided strong evidence that the GNAS1 T393C genetic polymorphism inﬂuenced the prognosis in advanced non-small lung cancer with a worse outcome for C allele carriers.
GNAS1; Polymorphism; Advanced non-small cell lung cancer; Prognosis
Early detection of ovarian cancer remains a challenge due to widespread metastases and a lack of biomarkers for early-stage disease. This study was conducted to identify relevant biomarkers for both laparoscopic and serum diagnostics in ovarian cancer.
Bioinformatics analysis and expression screening in ovarian cancer cell lines were employed. Selected biomarkers were further validated in bio-specimens of diverse cancer types and ovarian cancer subtypes. For non-invasive detection, biomarker proteins were evaluated in serum samples from ovarian cancer patients.
Two kallikrein (KLK) serine protease family members (KLK6 and KLK7) were found to be significantly overexpressed relative to normal controls in most of the ovarian cancer cell lines examined. Overexpression of KLK6 and KLK7 mRNA was specific to ovarian cancer, in particular to serous and papillary serous subtypes. In situ hybridization and histopathology further confirmed significantly elevated levels of KLK6 and KLK7 mRNA and proteins in tissue epithelium and a lack of expression in neighboring stroma. Lastly, KLK6 and KLK7 protein levels were significantly elevated in serum samples from serous and papillary serous subtypes in the early stages of ovarian cancer, and therefore could potentially decrease the high “false negative” rates found in the same patients with the common ovarian cancer biomarkers human epididymis protein 4 (HE4) and cancer antigen 125 (CA-125).
KLK6 and KLK7 mRNA and protein overexpression is directly associated with early-stage ovarian tumors and can be measured in patient tissue and serum samples. Assays based on KLK6 and KLK7 expression may provide specific and sensitive information for early detection of ovarian cancer.
Electronic supplementary material
The online version of this article (doi:10.1186/s13048-014-0109-z) contains supplementary material, which is available to authorized users.
Biomarker; Ovarian cancer; Diagnostic; Early detection; Bioinformatics
The worldwide distribution of dengue is expanding, in part due to globalized traffic and trade. Aedes albopictus is a competent vector for dengue viruses (DENV) and is now established in numerous regions of Europe. Viremic travellers arriving in Europe from dengue-affected areas of the world can become catalysts of local outbreaks in Europe. Local dengue transmission in Europe is extremely rare, and the last outbreak occurred in 1927–28 in Greece. However, autochthonous transmission was reported from France in September 2010, and from Croatia between August and October 2010.
We compiled data on areas affected by dengue in 2010 from web resources and surveillance reports, and collected national dengue importation data. We developed a hierarchical regression model to quantify the relationship between the number of reported dengue cases imported into Europe and the volume of airline travellers arriving from dengue-affected areas internationally.
In 2010, over 5.8 million airline travellers entered Europe from dengue-affected areas worldwide, of which 703,396 arrived at 36 airports situated in areas where Ae. albopictus has been recorded. The adjusted incidence rate ratio for imported dengue into European countries was 1.09 (95% CI: 1.01–1.17) for every increase of 10,000 travellers; in August, September, and October the rate ratios were 1.70 (95%CI: 1.23–2.35), 1.46 (95%CI: 1.02–2.10), and 1.35 (95%CI: 1.01–1.81), respectively. Two Italian cities where the vector is present received over 50% of all travellers from dengue-affected areas, yet with the continuing vector expansion more cities will be implicated in the future. In fact, 38% more travellers arrived in 2013 into those parts of Europe where Ae. albopictus has recently been introduced, compared to 2010.
The highest risk of dengue importation in 2010 was restricted to three months and can be ranked according to arriving traveller volume from dengue-affected areas into cities where the vector is present. The presence of the vector is a necessary, but not sufficient, prerequisite for DENV onward transmission, which depends on a number of additional factors. However, our empirical model can provide spatio-temporal elements to public health interventions.
The global disease burden of dengue is staggering. Continuous expansion and vaccine failures illustrate the limitations of current dengue control efforts. Novel approaches and additional tools are required to combat and contain the disease. In Europe, dengue infections are rare and the last outbreak of dengue occurred in the late 1920s, in Greece. In 2010, however, local transmission occurred in France and Croatia. Based on 2010 data, we present a novel quantitative model of the risk of dengue importation for Europe. The 2010 model predicts the risk of dengue importation to be greatest for Milan, Rome and Barcelona in August, September and October, precisely when vector activity is the highest. With the current expansion of the vector in Europe, more cities are projected to be at risk in the future. Thus, the model based on 2010 data quantifies the likelihood and timing of importation. This approach employs global travel data to assess dengue importation risk in the EU and illustrates how quantitative models could tailor infectious disease control to certain regions and time periods.
To investigate the antitumor effects of targeting Src and tubulin in mucinous ovarian carcinoma.
The in vitro and in vivo effects and molecular mechanisms of KX-01, which inhibits Src pathway and tubulin polymerization, were examined in mucinous ovarian cancer models.
In vitro studies using RMUG-S and RMUG-L cell lines showed that KX-01 inhibited cell proliferation, induced apoptosis, arrested the cell cycle at the G2/M phase, and enhanced the cytotoxicity of oxaliplatin in the KX-01-sensitive cell line, RMUG-S. In vivo studies showed that KX-01 significantly decreased tumor burden in RMUG-S and RMUG-L mouse models relative to untreated controls, and the effects were greater when KX-01 was combined with oxaliplatin. KX-01 alone and in combination with oxaliplatin significantly inhibited tumor growth by reducing cell proliferation and inducing apoptosis in vivo. PTEN knock-in experiments in RMUG-L cells showed improved response to KX-01. Reverse phase protein array analysis showed that in addition to blocking downstream molecules of Src family kinases, KX-01 also activated acute stress-inducing molecules.
Our results showed that targeting both the Src pathway and tubulin with KX-01 significantly inhibited tumor growth in preclinical mucinous ovarian cancer models, suggesting that this may be a promising therapeutic approach for patients with mucinous ovarian carcinoma.
Ovarian carcinoma; Mucinous; Src kinase; Tubulin; KX-01
Genetic variation in immune-related genes, such as IL10 and TNF, have been associated with the development of non-Hodgkin lymphoma (NHL) in Caucasian populations. To test the hypothesis that IL10 and TNF polymorphisms may be associated with NHL risk in Asian populations, we genotyped 20 single nucleotide polymorphisms (SNPs) within the IL10 and TNF/LTA loci in three independent case–control studies (2635 cases and 4234 controls). IL10 rs1800871, rs1800872, and rs1800896 were genotyped in all three studies, while 5 of the remaining SNPs were genotyped in two studies, and 12 in a single study. IL10 rs1800896 was associated with B cell lymphoma [per-allele odds ratio (OR) = 1.25, 95 % confidence interval (CI) 1.08–1.45; ptrend = 0.003], specifically diffuse large B cell lymphoma (DLBCL) (per-allele OR = 1.29, 95 % CI 1.08–1.53; ptrend = 0.004), as well as T cell lymphoma (per-allele OR = 1.44, 95 % CI 1.13–1.82; ptrend = 0.003). TNF rs1800629, which was genotyped in only two of our studies, was also associated with B cell lymphoma (per-allele OR = 0.77, 95 % CI 0.64–0.91; ptrend = 0.003), specifically DLBCL (per-allele OR = 0.69, 95 % CI 0.55–0.86; ptrend = 0.001). Our findings suggest that genetic variation in IL10 and TNF may also play a role in lymphomagenesis in Asian populations.
NHL; DLBCL; Subtype; Asia; IL10; TNF
The purpose of this study was to investigate whether transcatheter renal sympathetic denervation (RSD) interfere with the development of left ventricular (LV) mechanical dyssynchrony during the progression of heart failure (HF).
Nineteen beagles were randomly divided into sham-operated group (six dogs), control group (seven dogs), and RSD group (six dogs). Sham-operated group were implanted with pacemakers without pacing; Control group were implanted with pacemakers and underwent 3 weeks of rapid right ventricular pacing; and RSD group underwent catheter-based RSD bilaterally and were simultaneously implanted with pacemakers. Both LV strain and LV dyssynchrony were analyzed via 2D speckle-tracking strain echocardiography to evaluate LV function. Longitudinal dyssynchrony was determined as the standard deviation for time-to-peak speckle-tracking strain on apical 4- and 2-chamber views. Radial and circumferential dyssynchrony was determined as the standard deviation for time-to-peak speckle-tracking strain in mid- and base-LV short-axis views. Each myocardial function was also evaluated by averaging the peak systolic strains. LV systolic pressure (LVSP) and LV end-diastolic pressure (LVEDP) were measured. The LV interstitial fibrosis was determined by histological analysis. Plasma angiotensin II (Ang II), aldosterone and norepinephrine (NE) levels were also measured.
After 3 weeks, all of the dogs in both the control and RSD groups showed greater LV end-diastolic volume compared with the sham-operated group; however, the dogs in the RSD group had a higher LV ejection fraction (LVEF) than the dogs in the control group (p < 0.001). The LV systolic strains were higher in the RSD group than in the control group (p < 0.001 for longitudinal, circumferential and radial strain, respectively). The levels of LV dyssynchrony were lower in the RSD group than in the control group (p < 0.001 for longitudinal, circumferential and radial dyssynchrony, respectively). Compared with dogs with control alone, RSD dogs had lower LV end-diastolic pressures and less fibrous tissue. The levels of plasma Ang II, aldosterone and NE were lower in the RSD group than in the control group.
RSD inhibites the development of left ventricular mechanical dyssynchrony during the progression of heart failure in dogs.
Renal nerve ablation; Sympathetic nervous system; Heart failure; Ventricular dyssynchrony
Obstructive sleep apnea (OSA) is highly associated with hypertension. However, the correlation between hypertension and OSA at different levels of severity and the influence of gender on that correlation are unclear. A total of 996 patients (776 males and 190 females) with OSA were recruited. The influence of gender on the correlation between hypertension and OSA at different stratifications of severity, based on the apnea-hypopnea index (AHI), was fully evaluated together with the major health risk factors obesity, age, and diabetes. Females with OSA were significantly older on average than males with OSA. Moreover, females had milder degrees of OSA on average than the extent of severity seen in males. The proportion of females with diabetes or hypertension was higher than that of males. The proportion of males with hypertension and obesity increased significantly with OSA, and age also increased with OSA. The percentage of females with hypertension at different degrees of OSA severity was stable at about 26% in the mild, moderate, and severe OSA groups. Among females, age was increased significantly in the moderate relative to the mild OSA group. Moreover, the proportion of obese subjects was increased significantly in the severe compared with the moderate OSA group. The proportions of males and females with diabetes were not significantly different among all OSA severity groups. An ordinal multivariate logistic regression analysis confirmed that hypertension, age, and obesity were associated with OSA severity in males, whereas only age and obesity were associated with OSA severity in females. Although the proportion of subjects with hypertension was higher in females with OSA than in males with OSA, the proportion of subjects with hypertension increased as the severity of OSA increased in males but not in females.
Background. Cancer is a significant disease burden in the world. Many studies showed that heavy metals or their compounds had connection with cancer. But the data conflicting about the relationship of manganese (Mn) to cancer are not enough. In this paper, the relationship was discussed between Mn concentrations in drinking water for rural residents and incidence and mortality caused by malignant tumors in Huai'an city. Methods. A total of 158 water samples from 28 villages of 14 towns were, respectively, collected during periods of high flow and low flow in 3 counties of Huai'an city, along Chinese Huai'he River. The samples of deep groundwater, shallow groundwater, and surface water were simultaneously collected in all selected villages. Mn concentrations in all water samples were determined by inductively coupled plasma-mass spectrometry (ICP-MS 7500a). The correlation analysis was used to study the relationship between the Mn concentration and cancer incidence and mortality. Results. Mn concentrations detectable rate was 100% in all water samples. The mean concentration was 452.32 μg/L ± 507.76 μg/L. There was significant difference between the high flow period and low flow period (t = −5.23, P < 0.05) and also among deep groundwater, shallow groundwater, and surface water (F = 5.02, P < 0.05). The ratio of superscale of Mn was 75.32%. There was significant difference of Mn level between samples in the high flow period and low flow period (χ2 = 45.62, P < 0.05) and also among deep groundwater, shallow groundwater, and surface water (χ2 = 10.66, P < 0.05). And also we found that, during the low flow period, Mn concentration has positive correlation with cancer incidence and mortality; for a 1 μg/L increase in Mn concentration, there was a corresponding increase of 0.45/100000 new cancer cases and 0.35/100000 cancer deaths (P < 0.05). Conclusions. In Huai'an city, the mean concentration of Mn in drinking water was very high. Mn concentration correlated with cancer incidence and mortality.
Lung cancer in never smokers, which has been partially attributed to household solid fuel use (i.e coal), is etiologically and clinically different from lung cancer attributed to tobacco smoking. To explore the spectrum of driver mutations among lung cancer tissues from never smokers, specifically in a population where high lung cancer rates have been attributed to indoor air pollution from domestic coal use, multiplexed assays were used to detect >40 point mutations, insertions, and deletions (EGFR, KRAS, BRAF, HER2, NRAS, PIK3CA, MEK1, AKT1, and PTEN) among the lung tumors of confirmed never smoking females from Xuanwei, China [32 adenocarcinomas (ADCs), 7 squamous cell carcinomas (SCCs), 1 adenosquamous carcinoma (ADSC)]. EGFR mutations were detected in 35% of tumors. 46% of these involved EGFR exon 18 G719X, while 14% were exon 21 L858R mutations. KRAS mutations, all of which were G12C_34G>T, were observed in 15% of tumors. EGFR and KRAS mutations were mutually exclusive, and no mutations were observed in the other tested genes. Most point mutations were transversions and were also found in tumors from patients who used coal in their homes. Our high mutation frequencies in EGFR exon 18 and KRAS and low mutation frequency in EGFR exon 21 are strikingly divergent from those in other smoking and never smoking populations from Asia. Given that our subjects live in a region where coal is typically burned indoors, our findings provide new insights into the pathogenesis of lung cancer among never smoking females exposed to indoor air pollution from coal.
EGFR; KRAS; lung cancer; never smoking; China; driver mutations; tumor tissue
The properties of the screened mutants for hyper-production of citric acid induced by carbon (12C6+) ion beams and X-ray irradiation were investigated in our current study. Among these mutants, mutant H4002 screened from 12C6+ ion irradiation had a higher yield of citric acid production than the parental strain in a 250-ml shaking flash. These expanded submerged experiments in a bioreactor were also carried out for mutant H4002. The results showed that (177.7–196.0) g/L citric acid was accumulated by H4002 through exploiting corn meal hydrolysate (containing initial 200.0–235.7 g/L sugar) with the productivity of (2.96–3.27) g/(L∙h). This was especially true when the initial sugar concentration was 210 g/L, and the best economical citric acid production reached (187.5±0.7) g/L with a productivity of 3.13 g/(L∙h). It was observed that mutant H4002 can utilize low-cost corn meal as a feedstock to efficiently produce citric acid. These results imply that the H4002 strain has the industrial production potentiality for citric acid and offers strong competition for the citric acid industry.
Mutation; Citric acid; Corn meal hydrolysate; Aspergillus niger
The present study was carried out to investigate the hypothesis that organic nitrates can attenuate the senescence of mesenchymal stem cells (MSCs), a superior cell source involved in the regeneration and repair of damaged tissue. MSCs were treated with high glucose (HG) in order to induce senescence, which was markedly attenuated by pre-treatment with isosorbide dinitrate (ISDN), a commonly used nitrate, as indicated by senescence-associated galactosidase (SA-β-gal) activity, p21 expression, as well as by the mRNA levels of DNA methyltransferase 1 (DNMT1) and differentiated embryo chondrocyte expressed gene 1 (DEC1), which are senescence-related biomarkers. It was also found that the senescent MSCs (induced by HG glucose) exhibited a marked downregulation in ERK activity and forkhead box M1 (FOXM1) expression, which was reversed by ISDN preconditioning. Of note, the inhibition of ERK phosphorylation or the downregulation of FOXM1 statistically abolished the favourable effects of ISDN. In addition, the investigation of the senescence-associated miR-130 family suggested that miR-130b mediates the beneficial effects of ISDN; it was found that the protective effects of ISDN against the senescence of MSCs were prominently reversed by the knockdown of miR-130b. Furthermore, the downregulation of ERK phosphorylation or FOXM1 expression decreased the miR-130b expression level; however, the suppression of miR-130b demonstrated no significant impact on ERK phosphorylation or FOXM1 expression. Taken together, to the best of our knowledge, the present study is the first to demonstrate the favourable effects of ISDN against HG-induced MSC senescence, which are mediated through the activation of the ERK/FOXM1 pathway and the upregulation of miR-130b.
mesenchymal stem cell; senescence; hyperglycemia; nitrate; mechanism
Cyclic AMP (cAMP)-protein kinase A (PKA) signaling has been implicated in the regulation of ethanol consumption. Phosphodiesterase-4 (PDE4) specifically hydrolyzes cAMP and plays a critical role in controlling intracellular cAMP levels in the brain. However, the role of PDE4 in ethanol consumption remains unknown.
To examine whether PDE4 was involved in regulating ethanol intake.
The two-bottle choice paradigm was used to assess intake of ethanol, sucrose, and quinine in C57BL/6J mice treated with the selective PDE4 inhibitor rolipram or Ro 20-1724; locomotor activity was also monitored using the open-field test in mice treated with rolipram.
Administration (i.p.) of either rolipram (0.25 and 0.5 mg/kg) or Ro 20-1724 (10 mg/kg) reduced ethanol intake and preference by 60-80%, but did not alter total fluid intake. In contrast, rolipram even at the higher dose of 0.5 mg/kg was not able to affect intake of sucrose or quinine, alcohol-induced sedation, or blood ethanol elimination. At 0.5 mg/kg, rolipram did decrease locomotor activity, but the effect only lasted for approximately 40 min, which did not likely affect behavior of ethanol drinking.
These results suggest that PDE4 is a novel target for drugs that reduce ethanol intake; PDE4 inhibitors may be used for treatment of alcohol dependence.
Ethanol intake; phosphodiesterase-4 (PDE4); two-bottle choice; rolipram; locomotor activity; sucrose; quinine; cyclic AMP; mice
Several APOBEC3 proteins, particularly APOBEC3D, APOBEC3F, and APOBEC3G, induce G-to-A hypermutations in HIV-1 genome, and abrogate viral replication in experimental systems, but their relative contributions to controlling viral replication and viral genetic variation in vivo have not been elucidated. On the other hand, an HIV-1-encoded protein, Vif, can degrade these APOBEC3 proteins via a ubiquitin/proteasome pathway. Although APOBEC3 proteins have been widely considered as potent restriction factors against HIV-1, it remains unclear which endogenous APOBEC3 protein(s) affect HIV-1 propagation in vivo. Here we use a humanized mouse model and HIV-1 with mutations in Vif motifs that are responsible for specific APOBEC3 interactions, DRMR/AAAA (4A) or YRHHY/AAAAA (5A), and demonstrate that endogenous APOBEC3D/F and APOBEC3G exert strong anti-HIV-1 activity in vivo. We also show that the growth kinetics of 4A HIV-1 negatively correlated with the expression level of APOBEC3F. Moreover, single genome sequencing analyses of viral RNA in plasma of infected mice reveal that 4A HIV-1 is specifically and significantly diversified. Furthermore, a mutated virus that is capable of using both CCR5 and CXCR4 as entry coreceptor is specifically detected in 4A HIV-1-infected mice. Taken together, our results demonstrate that APOBEC3D/F and APOBEC3G fundamentally work as restriction factors against HIV-1 in vivo, but at the same time, that APOBEC3D and APOBEC3F are capable of promoting viral diversification and evolution in vivo.
Mutation can produce three outcomes in viruses: detrimental, neutral, or beneficial. The first one leads to abrogation of virus replication because of error catastrophe, while the last one lets the virus escape from anti-viral immune system or adapt to the host. Human APOBEC3D, APOBEC3F, and APOBEC3G are cellular cytidine deaminases which cause G-to-A mutations in HIV-1 genome. Here we use a humanized mouse model and demonstrate that endogenous APOBEC3F and APOBEC3G induce G-to-A hypermutation in viral genomes and exert strong anti-HIV-1 activity in vivo. We also reveal that endogenous APOBEC3D and/or APOBEC3F induce viral diversification, which can lead to the emergence of a mutated virus that converts its coreceptor usage. Our results suggest that APOBEC3D and APOBEC3F are capable of promoting viral diversification and functional evolution in vivo.
Background: Asthenozoospermia is one kind cause of male infertility. Nevertheless, no specific etiology can be identified by routine tests in some cases. Recently, it has been shown that leptin plays a critical role in male fertility. However, the link between leptin and sperm motility is yet to be determined. The aim of this study was to explore association between seminal and serum leptin levels and sperm motility in idiopathic asthenozoospermia. Methods: Our study included 79 asthenozoospermic men and 77 normozoospermic men. Semen was assessed by volume, sperm concentration, motility and morphology. Serum gonadotropic and sex hormones were determined by a chemiluminescent assay. The leptin levels in serum and seminal plasma were detected with ELISA. Results: The mean seminal leptin level in asthenozoospermic group was significantly higher than that in control group, but there was no significant difference in the serum leptin levels between these two groups. The serum leptin had no significant correlation with sperm motility. The seminal leptin had significantly negative correlation with sperm progressive motility and serum total testosterone. Conclusions: The findings indicate a pathophysiological relevance of seminal leptin in sperm motility.
Idiopathic asthenozoospermia; seminal leptin; serum leptin; sperm motility
It has been demonstrated that atrial electrical remodeling contributes toward atrial fibrillation (AF) maintenance, and that angiotensin II (AngII) is involved in the pathogenesis of atrial electrical remodeling. Peroxisome proliferator activated receptor-γ (PPAR-γ) agonists have been shown to inhibit atrial electrical remodeling, but the underlying mechanisms are poorly understood. In the present study we investigated the regulating effects of PPAR-γ agonist on AngII-induced potassium channel remodeling in atrial myocytes.
Whole-cell patch-clamp technique was used to record transient outward potassium current (Ito), ultra-rapid delayed rectifier potassium (Ikur), and inward rectifier potassium current (Ik1). Real-time PCR was used to assess potassium channel subunit mRNA expression.
Compared with the control group, AngII reduced Ito and Ikur current density as well as amplified Ik1 current density, which were partially prevented by pioglitazone. Furthermore, pioglitazone alleviated the downregulation of Ito subunit (Kv 4.2) and Ikur subunit (Kv 1.5), as well as the upregulation of Ik1 subunit (Kir 2.1 and Kir 2.2) mRNA expression stimulated by AngII.
These results suggest that pioglitazone exhibits a beneficial effect on AngII-induced potassium channel remodeling. PPAR-γ agonists may be potentially effective up-stream therapies for AF.
Angiotensin II; Atrial Fibrillation; Atrial Remodeling; Potassium Channels; PPAR gamma
We previously found focal adhesion kinase (FAK) inhibition sensitizes ovarian cancer to taxanes; however, the mechanisms are not well understood.
We characterized the biologic response of taxane-resistant and taxane-sensitive ovarian cancer models to a novel FAK inhibitor (VS-6063). We used reverse-phase protein arrays (RPPA) to identify novel downstream targets in taxane-resistant cell lines. Furthermore, we correlated clinical and pathological data with nuclear and cytoplasmic expression of FAK and YB-1 in 105 ovarian cancer samples. Statistical tests were two-sided, and P values were calculated with Student t test or Fisher exact test.
We found that VS-6063 inhibited FAK phosphorylation at the Tyr397 site in a time- and dose-dependent manner. The combination of VS-6063 and paclitaxel markedly decreased proliferation and increased apoptosis, which resulted in 92.7% to 97.9% reductions in tumor weight. RPPA data showed that VS-6063 reduced levels of AKT and YB-1 in taxane-resistant cell lines. FAK inhibition enhanced chemosensitivity in taxane-resistant cells by decreasing YB-1 phosphorylation and subsequently CD44 in an AKT-dependent manner. In human ovarian cancer samples, nuclear FAK expression was associated with increased nuclear YB-1 expression (χ
2 = 37.7; P < .001). Coexpression of nuclear FAK and YB-1 was associated with statistically significantly worse median overall survival (24.9 vs 67.3 months; hazard ratio = 2.64; 95% confidence interval = 1.38 to 5.05; P = .006).
We have identified a novel pathway whereby FAK inhibition with VS-6063 overcomes YB-1–mediated paclitaxel resistance by an AKT-dependent pathway. These findings have implications for clinical trials aimed at targeting FAK.